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Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model
Davide Caredio1, Giovanni Mariutti1, Lisa Polzer1
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Abstract:
Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.
Insights
A novel microglial state, marked by high Gpnmb expression, becomes active during neurodegeneration. This state is triggered by dying cells, not protein aggregates, revealing a key response to brain cell loss.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neurodegenerative diseases involve specific brain regions and glial cell alterations.
- Microglia, the brain's immune cells, play a crucial role in disease pathogenesis.
Purpose of the Study:
- To identify and characterize novel microglial states in neurodegeneration.
- To understand the triggers and mechanisms of microglial activation in response to cell death.
Main Methods:
- Analysis of microglial gene expression in prion-infected mouse models.
- Spatial distribution analysis of specific microglial populations.
- Investigation of factors inducing microglial states.
Main Results:
- Identified a distinct microglial state (Gpnmb+ microglia) with high Gpnmb expression and phagocytic signatures.
- This state is spatially associated with regions of significant cell death.
- The Gpnmb+ microglial state is induced by soluble factors from dying cells, independent of pathological protein aggregates.
Conclusions:
- Gpnmb+ microglia represent a specific phagocytic state linking cell death to microglial activation.
- Microglia respond to cell loss through a generalizable mechanism involving soluble factors from dying cells.
- This finding offers insights into glial cell responses in neurodegenerative disorders.
